VEGFR-2 and VEGFR-3 inhibitory anthranilamide pyridines

ABSTRACT

VEGFR-2 and VEGFR-3 inhibitory anthranilamide pyridinamides, their production and use as pharmaceutical agents for treating diseases that are triggered by persistent angiogenesis, as well as intermediate products for the production of the compounds are described. The compounds according to the invention can be used as or in the case of tumor or metastasis growth, psoriasis, Kaposi&#39;s sarcoma, restenosis, such as, e.g., stent-induced restenosis, endometriosis, Crohn&#39;s disease, Hodgkin&#39;s disease, leukemia; arthritis, such as rheumatoid arthritis, hemangioma, angiofibroma; eye diseases, such as diabetic retinopathy, neovascular glaucoma; renal diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopathic syndrome, transplant rejections and glomerulopathy; fibrotic diseases, such as cirrhosis of the liver, mesangial cell proliferative diseases, arteriosclerosis, injuries to nerve tissue, and inhibition of the reocclusion of vessels after balloon catheter treatment, in vascular prosthetics or after mechanical devices are used to keep vessels open, such as, e.g., stents, as immunosuppressive agents, as a support in scar-free healing, senile keratosis and contact dermatitis. The compounds according to the invention can also be used as VEGFR-3 inhibitors in the case of lymphangiogenesis.

This application claims benefit of U.S. Provisional Application No.60/407,970 filed on Sep. 5, 2002 and U.S. Provisional Application No.60/483,896, filed on Jul. 2, 2003.

The invention relates to VEGFR-2 and VEGFR-3 inhibitory anthranilamidepyridines, their production and use as pharmaceutical agents fortreating diseases that are triggered by persistent angiogenesis as wellas intermediate products for the production of compounds.

Persistent angiogenesis can be the cause or precondition of variousdiseases, such as tumor or metastasis growth, psoriasis; arthritis, suchas rheumatoid arthritis, hemangioma, angiofibroma; eye diseases, such asdiabetic retinopathy, neovascular glaucoma; renal diseases, such asglomerulonephritis, diabetic nephropathy, malignant nephrosclerosis,thrombic microangiopathic syndrome, transplant rejections andglomerulopathy; fibrotic diseases, such as cirrhosis of the liver,mesangial cell proliferative diseases and arteriosclerosis, or canresult in an aggravation of these diseases.

Persistent angiogenesis is induced by the factor VEGF via its receptor.So that VEGF can exert this action, it is necessary that VEGF bind tothe receptor, and a tyrosine phosphorylation is induced.

Direct or indirect inhibition of the VEGF receptor (VEGF=vascularendothelial growth factor) can be used for treating such diseases andother VEGF-induced pathological angiogenesis and vascular permeableconditions, such as tumor vascularization. For example, it is known thatthe growth of tumors can be inhibited by soluble receptors andantibodies against VEGF.

Anthranilamide pyridones that are used as pharmaceutical agents fortreating psoriasis; arthritis, such as rheumatoid arthritis, hemangioma,angiofibroma; eye diseases, such as diabetic retinopathy, neovascularglaucoma; renal diseases, such as glomerulonephritis, diabeticnephropathy, malignant nephrosclerosis, thrombic microangiopathicsyndrome, transplant rejections and glomerulopathy; fibrotic diseases,such as cirrhosis of the liver, mesangial cell proliferative diseases,arteriosclerosis, injuries to nerve tissue, and for inhibiting thereocclusion of vessels after balloon catheter treatment, in vascularprosthetics or after mechanical devices are used to keep vessels open,such as, e.g., stents, are known from WO 00/27820 (e.g., Example 38).

The compounds that are known from WO 00/27820 are generally effective inthe indications cited, but their effectiveness is not very pronounced.

Anthranilic acid amides that are are highly effective but also have agood inhibition of the Cytochrome P 450 isoenzyme 3A4 are also knownfrom WO 00/27819 (Example 2.54). The Cytochrome P 450 isoenzyme 3A4 isone of the essential metabolic enzymes via which pharmaceutical agentsare degraded. An inhibition of this isoenzyme results in undesirablepharmaceutical agent interactions, especially in the case of multimorbidpatients (patients with multiple disease conditions). There also existsthe problem that in a combination therapy with other medications,increased toxicity occurs, which results from the inhibition of thedegradation of the compounds and the associated excessive serum levels.

There is therefore the desire for active ingredients that on the onehand are effective and on the other hand are more compatible or do notexhibit any undesirable side effects.

There is therefore a desire for, on the one hand, more effective, and,on the other hand, more compatible compounds.

-   -   It has now been found that compounds of general formula I

in which

-   -   X stands for CH or N,    -   W stands for hydrogen or fluorine,    -   A, B, D,    -   E and Q, in each case independently of one another, stand for a        nitrogen or carbon atom, whereby only a maximum of two nitrogen        atoms can be present in the ring,    -   R¹ stands for aryl or heteroaryl, which optionally can be        substituted in one or more places in the same way or differently        with halogen, hydroxy, C₁–C₁₂-alkyl, C₃–C₆-cycloalkyl,        C₃–C₆-alkenyl, C₂–C₆-alkinyl, aralkyloxy, C₁–C₁₂-alkoxy,        halo-C₁–C₆-alkyl, cyano-C₁–C₆-alkyl or with the group ═O, —SO₂R⁶        or —OR⁵, whereby the C₁–C₆-alkyl optionally also can be        substituted with the group —OR⁵ or —NR⁹R¹⁰,    -   Y and Z, in each case independently of one another, stand for a        bond or for the group ═CO, ═CS or ═SO₂,    -   R² and R³, independently of one another, stand for hydrogen or        for the group —CONR⁹R¹⁰, —SO²R⁶, —COR¹¹, —COC₁–C₆-alkyl,        —CO—C₁–C₆-alkyl-R¹¹, —NR⁹R¹⁰ or for C₁–C₆-alkyl,        C₃–C₁₀-cycloalkyl, C₃–C₆-cycloalkenyl, aryl or heteroaryl that        is optionally substituted in one or more places in the same way        or differently with halogen, cyano, C₁–C₁₂-alkyl, C₁–C₁₂-alkoxy,        hydroxy-C₁–C₆-alkyl, halo-C₁–C₆-alkyl or with the group —NR⁷R⁸,        —OR⁵, —C₁–C₆-alkyl-OR⁵, —SR⁴, —SOR⁴ or —SO₂R⁶, or    -   R², R³, Y    -   and Z together with the nitrogen atom form a 3- to 8-membered        saturated or unsaturated ring, which optionally can contain        additional heteroatoms in the ring and optionally can be        substituted in one or more places in the same way or differently        with halogen, cyano, C₁–C₁₂-alkyl, C₁–C₁₂-alkoxy,        halo-C₁–C₆-alkyl, hydroxy-C₁–C₆-alkyl, or with the group ═O,        —OR⁵, —SR⁴, —SOR⁴ or —SO₂R⁶,    -   R⁴ stands for C₁–C₁₂-alkyl, aryl or heteroaryl,    -   R⁵ stands for hydrogen, C₁–C₁₂-alkyl, C₃–C₁₀-cycloalkyl,        C₁–C₁₂-alkoxy, halo-C₁–C₁₂-alkyl, or halo-C₃–C₆-cycloalkyl,    -   R⁶ stands for hydrogen, C₁–C₁₂-alkyl, halo-C₁–C₆-alkyl, aryl or        heteroaryl, or for the group —NR⁹R¹⁰, whereby the aryl or        heteroaryl itself optionally can be substituted in one or more        places in the same way or differently with C₁–C₁₂-alkyl,        C₁–C₆-alkoxy, halogen or halo-C₁–C₆-alkoxy,    -   R⁷ and R⁸, independently of one another, stand for hydrogen or        C₁–C₁₂-alkyl,    -   R⁹ and R¹⁰, independently of one another, stand for hydrogen,        C₁–C₆-alkyl, C₂–C₆-alkenyl, aryl, C₃–C₈-cycloalkyl or for the        group —CONR⁷R⁸, or for C₁–C₁₂-alkyl that is optionally        substituted in one or more places in the same way or differently        with aryl, morpholino, hydroxy, halogen, C₁–C₁₂-alkoxy, or with        the group —NR⁷R⁸, whereby the aryl itself optionally can be        substituted in one or more places in the same way or differently        with C₁–C₆-alkoxy or halo-C₁–C₆-alkyl, or    -   R⁹ and R¹⁰ together form a 5- to 8-membered ring that can        contain additional heteroatoms, and    -   R¹¹ stands for C₁–C₆-alkyl, C₁–C₆-alkoxy, hydroxy-C₁–C₆-alkyl,        hydroxy-C₁–C₆-alkoxy, C₃–C₆-cycloalkyl, phenyl, pyridyl,        biphenyl or naphthyl, whereby the phenyl itself can be        substituted in one or more places in the same way or differently        with C₁–C₆-alkyl, or halo-C₁–C₆-alkyl, as well as isomers,        diastereomers, tautomers and salts thereof,        exhibit improved properties, i.e., high effectiveness with        simultaneously less CYP450 3A4 inhibition.

The compounds according to the invention prevent a tyrosinephosphorylation or stop persistent angiogenesis and thus the growth andpropagation of tumors, whereby they are distinguished in particular by aslighter inhibition of isoforms of Cytochrome P 450 (3A4).

Medication using the compounds according to the invention can thereforealso be done at no risk even without regard to pharmaceutical agentsthat are administered at the same time and that are degraded via theseisoforms.

Alkyl is defined in each case as a straight-chain or branched alkylradical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, pentyl, isopentyl or hexyl, heptyl, octyl, nonyl,decyl, undecyl, or dodecyl.

Alkoxy is defined in each case as a straight-chain or branched alkoxyradical, such as, for example, methyloxy, ethyloxy, propyloxy,isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, pentyloxy,isopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy,undecyloxy or dodecyloxy.

Cycloalkyls are defined as monocyclic alkyl rings, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, cyclooctyl,cyclononyl or cyclodecyl, but also bicyclic rings or tricyclic rings,such as, for example, adamantanyl.

Cycloalkyl radicals can contain, instead of the carbon atoms, one ormore heteroatoms, such as oxygen, sulfur and/or nitrogen. Thoseheterocycloalkyls with 3 to 8 ring atoms are preferred.

Cycloalkenyl is defined in each case as cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl,whereby the linkage can be carried out both to the double bond and tothe single bonds.

Halogen is defined in each case as fluorine, chlorine, bromine oriodine.

Halo-alkyl, halo-alkoxy, etc., is defined in that the alkyl, alkoxy,etc., is substituted in one or more places, in the same way ordifferently, with halogen.

Alkenyl is defined in each case as a straight-chain or branched alkenylradical that contains 2–6, preferably 4–6, C atoms. For example, thefollowing radicals can be mentioned: vinyl, propen-1-yl, propen-2-yl,but-1-en-1-yl, but-1-en-2-yl, but-2-en-1-yl, but-2-en-2-yl,2-methyl-prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, but-1-en-3-yl,but-3-en-1-yl, and allyl.

The aryl radical in each case comprises 3–12 carbon atoms and can ineach case be benzocondensed.

For example, there can be mentioned: cyclopropenyl, cyclopentadienyl,phenyl, tropyl, cyclooctadienyl, indenyl, naphthyl, azulenyl, biphenyl,fluorenyl, anthracenyl, etc.

The heteroaryl radical in each case comprises 3–16 ring atoms, andinstead of the carbon can contain one or more heteroatoms that are thesame or different, such as oxygen, nitrogen or sulfur, in the ring, andcan be monocyclic, bicyclic, or tricyclic, and in addition in each casecan be benzocondensed.

For example, there can be mentioned:

Thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc.,and benzo derivatives thereof, such as, e.g., benzofuranyl,benzothienyl, benzoxazolyl, benzimidazolyl, indazolyl, indolyl,isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,triazinyl, etc., and benzo derivatives thereof, such as, e.g., quinolyl,isoquinolyl, etc.; or azocinyl, indolizinyl, purinyl, etc., and benzoderivatives thereof; or quinolinyl, isoquinolinyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl,carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,xanthenyl, or oxepinyl, etc.

The heteroaryl radical can be benzocondensed in each case. For example,there can be mentioned as 5-ring heteroaromatic compounds: thiophene,furan, oxazole, thiazole, imidazole, pyrazole and benzo derivativesthereof, and as 6-ring heteroaromatic compounds: pyridine, pyrimidine,triazine, quinoline, isoquinoline and benzo derivatives.

Heteroatoms are defined as oxygen, nitrogen or sulfur atoms.

A 3- to 8-membered ring in the meaning of R², R³, Y and Z, which isformed together with the nitrogen atom, is defined asC₃–C₈-cycloheteroalkyls and C₃–C₈-heteroaryls.

If an acid group is included, the physiologically compatible salts oforganic and inorganic bases are suitable as salts, such as, for example,the readily soluble alkali salts and alkaline-earth salts as well asN-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine,1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol,tris-hydroxy-methyl-amino-methane, aminopropanediol, Sovak base, and1-amino-2,3,4-butanetriol.

If a basic group is included, the physiologically compatible salts oforganic and inorganic acids are suitable, such as hydrochloric acid,sulfuric acid, phosphoric acid, citric acid, tartaric acid, fumaricacid, i.a.

The compounds of general formula I according to the invention alsocontain the possible tautomeric forms and comprise the E-isomers orZ-isomers, or, if a chiral center is present, also the racemates andenantiomers.

Those compounds of general formula I in which

-   -   X stands for CH,    -   W stands for hydrogen,    -   A, B, D,    -   E and Q as a ring together stand for pyridyl,    -   R¹ stands for aryl or heteroaryl, which optionally can be        substituted in one or more places in the same way or differently        with halogen, hydroxy, C₁–C₆-alkyl, C₃–C₆-cycloalkyl,        C₄–C₆-alkenyl, C₂–C₆-alkinyl, aralkyloxy, C₁–C₆-alkoxy,        halo-C₁–C₆-alkyl, cyano-C₁–C₆-alkyl, or with the group ═O,        —SO₂R⁶ or —OR⁵, whereby C₁–C₆-alkyl optionally also can be        substituted with the group —OR⁵ or —NR⁹R¹⁰,    -   Y and Z, in each case independently of one another, stand for a        bond,    -   R² and R³, independently of one another, stand for hydrogen or        for the group —CONR⁹R¹⁰, —SO₂R⁶, —COR¹¹, —COC₁–C₆-alkyl,        —CO—C₁–C₆-alkyl-R¹¹, —NR⁹R¹⁰ or for C₁–C₆-alkyl,        C₃–C₆-cycloalkyl, C₃–C₆-cycloalkenyl, aryl or heteroaryl that is        optionally substituted in one or more places in the same way or        differently with halogen, cyano, C₁–C₆-alkyl, C₁–C₆-alkoxy,        hydroxy-C₁–C₆-alkyl, halo-C₁–C₆-alkyl or with the group —NR⁷R⁸,        —OR⁵, —C₁–C₆-alkyl-OR⁵, —SR⁴, —SOR⁴ or —SO₂R⁶, or    -   R², R³, Y    -   and Z together with the nitrogen atom form a 3- to 8-membered        saturated or unsaturated ring, which optionally can contain        additional heteroatoms in the ring and optionally can be        substituted in one or more places in the same way or differently        with halogen, cyano, C₁–C₁₂-alkyl, C₁–C₁₂-alkoxy,        halo-C₁–C₆-alkyl, hydroxy-C₁–C₆-alkyl or with the group ═O,        —OR⁵, —SR⁴, —SOR⁴ or —SO₂R⁶,    -   R⁴ stands for C₁–C₆-alkyl, aryl or heteroaryl,    -   R⁵ stands for hydrogen, C₁–C₆-alkyl, halo-C₁–C₆-alkyl,        C₁–C₁₂-alkoxy, C₃–C₁₀-cycloalkyl or halo-C₃–C₆-cycloalkyl,    -   R⁶ stands for hydrogen, C₁–C₆-alkyl, halo-C₁–C₆-alkyl, aryl or        heteroaryl, or for the group —NR⁹R¹⁰, whereby the aryl or        heteroaryl itself optionally can be substituted in one or more        places in the same way or differently with C₁–C₆-alkyl,        C₁–C₆-alkoxy, halogen or halo-C₁–C₆-alkoxy,    -   R⁷ and R⁸, independently of one another, stand for hydrogen or        C₁–C₆-alkyl,    -   R⁹ and R¹⁰, independently of one another, stand for hydrogen,        C₁–C₆-alkyl, C₂–C₆-alkenyl, aryl, C₃–C₈-cycloalkyl, or for the        group —CONR⁷R⁸, or for C₁–C₆-alkyl that is optionally        substituted in one or more places in the same way or differently        with aryl, morpholino, hydroxy, halogen or C₁–C₁₂-alkoxy, or        with the group —NR⁷R⁸, whereby the aryl itself optionally can be        substituted in one or more places in the same way or differently        with C₁–C₆-alkoxy or halo-C₁–C₆-alkyl, and    -   R¹¹ stands for C₁–C₆-alkyl, C₁–C₆-alkoxy, hydroxy-C₁–C₆-alkyl,        hydroxy-C₁–C₆-alkoxy, C₃–C₆-cycloalkyl, phenyl, pyridyl,        biphenyl or naphthyl, whereby the phenyl itself can be        substituted in one or more places in the same way or differently        with C₁–C₆-alkyl, or halo-C₁–C₆-alkyl, as well as isomers,        diastereomers, tautomers and salts thereof, have proven        advantageous.

Those compounds of general formula I, in which

-   -   X stands for CH,    -   W stands for hydrogen,    -   A, B, D,    -   E, and Q as a ring together stand for pyridyl,    -   R¹ stands for phenyl, quinolinyl, isoquinolinyl or indazolyl,        which optionally can be substituted in one or more places in the        same way or differently with halogen, hydroxy, C₁–C₆-alkyl,        C₂–C₆-alkinyl, C₁–C₆-alkoxy, halo-C₁–C₆-alkyl, or        cyano-C₁–C₆-alkyl, whereby C₁–C₆-alkyl optionally also can be        substituted with the group —OR⁵ or —NR⁹R¹⁰,    -   Y and Z, in each case independently of one another, stand for a        bond, or for the group ═CO,    -   R² and R³, independently of one another, stand for hydrogen or        for the group —CONR⁹R¹⁰, —SO₂R⁶, —COR¹¹, —COC₁–C₆-alkyl,        —CO—C₁–C₆-alkyl-R¹¹, —NR⁹R¹⁰ or for C₁–C₆-alkyl or phenyl that        is optionally substituted in one or more places in the same way        or differently with the group —NR⁷R⁸ or —OR⁵, or    -   R², R³, Y    -   and Z together with the nitrogen atom form a 3- to 8-membered        saturated or unsaturated ring that optionally can contain        additional heteroatoms in the ring and optionally can be        substituted in one or more places in the same way or differently        with halogen, cyano, C₁–C₁₂-alkyl, C₁–C₁₂-alkoxy,        halo-C₁–C₆-alkyl, hydroxy-C₁–C₆-alkyl or with the group ═O,        —OR⁵, —SR⁴, —SOR⁴ or —SO₂R⁶,    -   R⁵ stands for hydrogen or C₁–C₆-alkyl,    -   R⁶ stands for hydrogen, C₁–C₆-alkyl, halo-C₁–C₆-alkyl, phenyl,        benzyl, thiophenyl, or pyridyl, whereby the phenyl, benzyl,        thiophenyl and pyridyl itself optionally can be substituted in        one or more places in the same way or differently with        C₁–C₆-alkyl, C₁–C₆-alkoxy, halogen or halo-C₁–C₆-alkoxy,    -   R⁷ and R⁸, independently of one another, stand for hydrogen or        C₁–C₆-alkyl,    -   R⁹ and R¹⁰, independently of one another, stand for hydrogen,        C₁–C₆-alkyl, C₂–C₆-alkenyl, phenyl, biphenyl, C₃–C₈-cycloalkyl,        naphthyl or for the group —CONR⁷R⁸ or for C₁–C₆-alkyl that is        optionally substituted in one or more places in the same way or        differently with phenyl, morpholino, hydroxy, halogen,        C₁–C₁₂-alkoxy, or with the group —NR⁷R⁸, whereby the phenyl        itself optionally can be substituted in one or more places in        the same way or differently with C₁–C₆-alkoxy or        halo-C₁–C₆-alkyl, and    -   R¹¹ stands for C₁–C₆-alkyl, C₁–C₆-alkoxy, hydroxy-C₁–C₆-alkyl,        hydroxy-C₁–C₆-alkoxy, C₃–C₆-cycloalkyl, phenyl, pyridyl,        biphenyl or naphthyl, whereby the phenyl itself can be        substituted in one or more places in the same way or differently        with C₁–C₆-alkyl, or halo-C₁–C₆-alkyl, as well as isomers,        diastereomers, tautomers and salts thereof,        are of special interest.

The compounds according to the invention as well as theirphysiologically compatible salts prevent a tyrosine phosphorylation orstop persistent angiogenesis and thus the growth and propagation oftumors, whereby they are distinguished in particular by a slighterinhibition of isoforms of Cytochrome P 450 (3A4). Medication using thecompounds according to the invention can therefore be done at no riskeven without regard to pharmaceutical agents that are administered atthe same time and that are degraded via these isoforms.

The compounds of formula I as well as their physiologically compatiblesalts can be used as pharmaceutical agents based on their inhibitoryactivity relative to the phosphorylation of the VEGF receptor. Based ontheir profile of action, the compounds according to the invention aresuitable for treating diseases that are caused or promoted by persistentangiogenesis.

Since the compounds of formula I are identified as inhibitors of thetyrosine kinases KDR and FLT, they are suitable in particular fortreating those diseases that are caused or promoted by persistentangiogenesis that is triggered via the VEGF receptor or by an increasein vascular permeability.

The subject of this invention is also the use of the compounds accordingto the invention as inhibitors of the tyrosine kinases KDR and FLT.

Subjects of this invention are thus also pharmaceutical agents fortreating tumors or use thereof.

The compounds according to the invention can be used either alone or ina formulation as pharmaceutical agents for treating tumor or metastasisgrowth, psoriasis, Kaposi's sarcoma, restenosis, such as, e.g.,stent-induced restenosis, endometriosis, Crohn's disease, Hodgkin'sdisease, leukemia; arthritis, such as rheumatoid arthritis, hemangioma,angiofibroma; eye diseases, such as diabetic retinopathy, neovascularglaucoma; renal diseases, such as glomerulonephritis, diabeticnephropathy, malignant nephrosclerosis, thrombic microangiopathicsyndrome, transplant rejections and glomerulopathy; fibrotic diseases,such as cirrhosis of the liver, mesangial cell proliferative diseases,arteriosclerosis, injuries to nerve tissue, and for inhibiting thereocclusion of vessels after balloon catheter treatment, in vascularprosthetics or after mechanical devices are used to keep vessels open,such as, e.g., stents, as immunosuppressive agents, for supportingscar-free healing, in senile keratosis and in contact dermatitis.

In treating injuries to nerve tissue, quick scar formation on the injurysites can be prevented with the compounds according to the invention,i.e., scar formation is prevented from occurring before the axonsreconnect. A reconstruction of the nerve compounds was thus facilitated.

The formation of ascites in patients can also be suppressed with thecompounds according to the invention. VEGF-induced edemas can also besuppressed.

Lymphangiogenesis plays an important role in lymphogenic metastasizing(Karpanen, T. et al., Cancere Res. 2001 Mar 1, 61(5): 1786–90, Veikkola,T., et al., EMBO J. 2001, Mar 15; 20 (6): 1223–31).

The compounds according to the invention now also show excellent actionas VEGFR kinase 3 inhibitors and are therefore also suitable aseffective inhibitors of lymphangiogenesis.

By a treatment with the compounds according to the invention, not only areduction of the size of metastases but also a reduction of the numberof metastases is achieved.

Such pharmaceutical agents, their formulations and uses are alsosubjects of this invention.

The invention thus also relates to the use of the compounds of generalformula I for the production of a pharmaceutical agent for use as or fortreatment of tumor or metastasis growth, psoriasis, Kaposi's sarcoma,restenosis, such as, e.g., stent-induced restenosis, endometriosis,Crohn's disease, Hodgkin's disease, leukemia; arthritis, such asrheumatoid arthritis, hemangioma, angiofibroma; eye diseases, such asdiabetic retinopathy, neovascular glaucoma; renal diseases, such asglomerulonephritis, diabetic nephropathy, malignant nephrosclerosis,thrombic microangiopathic syndrome, transplant rejections andglomerulopathy; fibrotic diseases, such as cirrhosis of the liver,mesangial cell proliferative diseases, arteriosclerosis, injuries tonerve tissue, and for inhibiting the reocclusion of vessels afterballoon catheter treatment, in vascular prosthetics or after mechanicaldevices are used to keep vessels open, such as, e.g., stents, asimmunosuppressive agents, as a support in scar-free healing, in senilekeratosis and in contact dermatitis.

The formation of ascites in patients can also be suppressed with thecompounds according to the invention. VEGF-induced edemas can also besuppressed.

To use the compounds of formula I as pharmaceutical agents, the latterare brought into the form of a pharmaceutical preparation, which inaddition to the active ingredient for enteral or parenteraladministration contains suitable pharmaceutical, organic or inorganicinert carrier materials, such as, for example, water, gelatin, gumarabic, lactose, starch, magnesium stearate, talc, vegetable oils,polyalkylene glycols, etc. The pharmaceutical preparations can bepresent in solid form, for example as tablets, coated tablets,suppositories, or capsules, or in liquid form, for example as solutions,suspensions or emulsions. They optionally contain, moreover, adjuvantssuch as preservatives, stabilizers, wetting agents or emulsifiers, saltsfor changing osmotic pressure or buffers.

For parenteral administration, especially injection solutions orsuspensions, especially aqueous solutions of the active compounds inpolyhydroxyethoxylated castor oil, are suitable.

As carrier systems, surface-active adjuvants such as salts of bile acidsor animal or plant phospholipids, but also mixtures thereof as well asliposomes or components thereof can also be used.

For oral administration, especially tablets, coated tablets or capsuleswith talc and/or hydrocarbon vehicles or binders, such as for example,lactose, corn starch or potato starch, are suitable. The administrationcan also be carried out in liquid form, such as, for example, as juice,to which optionally a sweetener or, if necessary, one or more flavoringsubstances, is added.

The dosage of the active ingredients can vary depending on the method ofadministration, age and weight of the patient, type and severity of thedisease to be treated and similar factors. The daily dose is 0.5–1000mg, preferably 50–200 mg, whereby the dose can be given as a single doseto be administered once or divided into 2 or more daily doses.

The above-described formulations and forms for dispensing are alsosubjects of this invention.

The production of the compounds according to the invention is carriedout according to methods that are known in the art. For example,compounds of general formula I are obtained in that a compound ofgeneral formula II

in which A, B, D, E, Q, W, X and R¹ have the meanings that are indicatedin general formula I, and M stands for halogen, first is converted intoan amine and then is acylated, or M is substituted by an NHCOR′ group.

Compounds of general formula I are also obtained in that a compound ofgeneral formula IIa,

in which R^(y) stands for C₁–C₆-alkyl or hydrogen, and FG means aleaving group, such as, e.g., halogen, O-triflate, O-mesylate,O-tosylate or sulfone, first is converted into an amide, and then theleaving group is substituted by an N(Y—R²)—R³ group, or a compound III

in which R², R³, Y and Z have the meanings that are indicated in generalformula I and R^(y) stands for C₁–C₆-alkyl or hydrogen, first issaponified and then is converted into the amide.

The amide formation is carried out according to methods that are knownin the literature.

For amide formation, it is possible to start from a corresponding ester.The ester is reacted according to J. Org. Chem. 1995, 8414 with aluminumtrimethyl and the corresponding amine in solvents such as toluene attemperatures of 0° C. to the boiling point of the solvent. If themolecule contains two ester groups, both are converted into the sameamide. Instead of aluminum trimethyl, sodium hexamethyldisilazide canalso be used.

For amide formation, however, all processes that are known from peptidechemistry are also available. For example, the corresponding acid can bereacted with the amine in aprotic polar solvents, such as, for example,dimethylformamide, via an activated acid derivative, that can beobtained, for example, with hydroxybenzotriazole and a carbodiimide,such as, for example, diisopropylcarbodiimide, at temperatures ofbetween 0° C. and the boiling point of the solvent, preferably at 80° C.The reaction between carboxylic acid and amine, however, can also beproduced by activation reagents, such as HATU(N-dimethylamino-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate-N-oxide), whereby polar aprotic solvents, such as,for example, dimethylformamide, are suitable for the reaction. Theaddition of a base such as N-methylmorpholine is necessary. The reactionproceeds at temperatures of 0–100° C., whereby the procedure ispreferably performed at room temperature, but in many cases heating isindispensable. For the amide formation, the process can also be usedwith the acid halide, the mixed acid anhydride, imidazolide or azide. Aprevious protection of an additional amino group, for example as anamide, is not necessary in all cases, but can advantageously influencethe reaction.

In the case of bisacid chlorides, cyclic compounds can be produced.Also, in the case of halogen acid halides, cyclic compounds can beproduced. The ring closure is then completed optionally by adding astrong base, such as, for example, sodium alcoholates. The same thingholds true for the sulfonic acid halides, whereby double sulfonationscan also occur.

Ureas are produced from amino compounds by reaction with isocyanates.Inert solvents such as methylene chloride or else dimethylformamide attemperatures from room temperature up to 100° C., preferably at 60° C.Pressure is advantageous for the reaction.

The reaction of halopyridines with amides is carried out undercatalysis, for example by palladium or copper catalysis. In the case ofcopper catalysis (literature, see Synlett. 2002, 427), solvents such asdioxane or dimethylformamide are used at temperatures up to the boilingpoint of the solvent, preferably 120° C. As a base, potassium phosphateor else cesium carbonate is used. Ethylenediamine is advantageous forcomplexing the copper(I) iodide that is used as a catalyst. Anapplication of pressure is not harmful. In the case of palladiumcatalysis, both palladium(II) salts, such as palladium(II) acetate, andpalladium(O) complexes, such as palladium(O)₂dibenzylidene acetone₃(literature, see JACS 2002, 6043, THL 1999, 2035, Org. Lett 2001, 2539,THL 2001, 4381 or THL 2001, 3681) can . . . . As a solvent, toluene,dioxane or dimethylformamide are used at temperatures from roomtemperature up to the boiling point of the solvent, preferably around100° C. As a co-ligand, BINAP, DPPF or Xanthphos are used. A base isalso necessary. To this end, cesium carbonate, potassium phosphate orelse sodium-t-butylate is used. These components can be combined invarious ways.

The production of the pyridinamines from the corresponding2-halopyridines is carried out in solvents such as pyridine or in proticpolar solvents such as ethylene glycol at temperatures up to 200° C.Catalysis by copper(I) salts can be necessary for the reaction. Theapplication of pressure is absolutely necessary in the case of thereaction of low-boiling amines, but can also be used advantageously inthe conventional amines.

The ether cleavage is accomplished according to known methods, forexample by reaction with boron tribromide in inert solvents, such asmethylene chloride, at temperatures of −78° C. up to room temperature,preferably at −78° C.

The compounds of general formulas II, IIa and III,

in which A, B, D, E, Q, W, X, Y, Z, R², and R³ have the meanings thatare indicated in general formula I and M stands for halogen, FG standsfor a leaving group, such as, e.g., halogen, O-triflate, O-mesylate,O-tosylate or sulfone, and R^(Y) stands for C₁–C₆-alkyl or hydrogen,represent valuable intermediate products for the production of thecompounds of general formula I according to the invention and are thusalso subjects of this invention.

PRODUCTION OF THE COMPOUNDS ACCORDING TO THE INVENTION

The following examples explain the production of the compounds accordingto the invention without the scope of the claimed compounds beinglimited to these examples.

EXAMPLE 1.0 Production of2-{[2-(2-Dimethylamino-ethylamino)-pyridin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-benzamide

90 mg (0.2 mmol) of2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamideis dissolved in 3 ml of pyridine and mixed with 1 ml ofN,N-dimethyl-aminoethylamine and heated in a pressure vessel for 5 hoursto a bath temperature of 200° C. After cooling, it is concentrated byevaporation, and 90 mg of2-{[2-(2-dimethylamino-ethylamino)-pyridin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-benzamideis obtained.

Melting point: 100° C.

Similarly produced are also the following compounds:

[Key: Typ = Type] Melting Point [° C.] or MS Exam- Molar Peak ple No.Type R² R³ R¹ MW (m/e) 1.1 A —(CH₂)₂—OH H

430.5 1.2 A —(CH₂)₂—OH H

413.5 130–132 1.3 A —(CH₂)₃OH H

444.5 148 1.4 A —(CH₂)₄OH H

458.5 124 1.5 A —(CH₂)₅OH H

472.5 70 1.6 A —(CH₂)₂OMe H

444.5 1.7 A

H

444.5 80 1.8 A

H

444.5 65 1.9 A

H

444.5 81 1.10 A (CH₂)₃NMe₂ H

471.5 68 1.11 B —(CH₂)₂—OH H

413.5 Resin 1.12 A Phenyl H

462.5 1.13 A —(CH₂)₅—

437.54 1.14 A —(CH₂)₂—O—(CH₂)₂—

439.52 174 1.15 A —(CH₂)₂—NMe—(CH₂)₂—

452.56 85 1.16 A —(CH₂)₂—S—(CH₂)₂—

455.58 158 1.17 A —(CH₂)₂—SO₂—(CH₂)₂—

487.58 1.18 A —(CH₂)₄—

423.52 148

EXAMPLE 2.0 Production of2-[(2-Amino-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamide

8.747 g (19.4 mmol) of2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamideis heated with 175 mg of copper(I) oxide in 150 ml of ethanediol for 23hours under 10 bar of ammonia pressure to 80° C. in an autoclave. Afterthe solvent is distilled off in a vacuum, the residue is purified onsilica gel with a gradient of ethyl acetate:ethanol=100:0 to 0:100 as aneluant. 4.15 g (51% of theory) of2-[(2-amino-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamidewith a melting point of 64° C. is obtained.

Similarly produced are:

EXAMPLE 2.12-[(2-Amino-pyridin-4-ylmethyl)-amino]-N-isoquinolin-3-yl-benzamide

Melting point: 202° C.

EXAMPLE 2.22-[(2-Amino-pyridin-4-ylmethyl)-amino]-N-(1H-indazol-5-yl)-benzamide

MS: m/e 358

Melting point: 200° C.

EXAMPLE 2.32-[(2-Amino-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benzamide

MW: 372.43

EXAMPLE 3.0 Production of2-{[2-(3-Benzyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-benzamide

100 mg (0.26 mmol) of2-[(2-amino-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamideis mixed in 2.5 ml of methylene chloride with 37.9 mg (0.29 mmol) ofbenzyl isocyanate, and it is stirred overnight at room temperature.After concentration by evaporation, the residue is chromatographed. 66mg (49% of theory) of2-{[2-(3-benzyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-benzamidewith a melting point of 153° C. is obtained.

Similarly produced are also the following compounds:

[Key: Typ = Type] Melting Point [° C.] or MS Exam- Molar Peak ple No.Type R¹ R¹⁰ MW (m/e) 3.1 A

Phenyl 505.5 185 3.2 A

Ph(CH₂)₂— 533.5 76 3.3 A

n-Butyl 485.5 84 3.4 A

595.5 206 3.5 A

573.5 186 3.6 A

573.5 211 3.7 A

Ethyl 457.5 154 3.8 A

581.6 195 3.9 A

555.5 180 3.10 A

—CH₃ 443.4 159 3.11 A

—CH₂CH₂Cl 491.9 157 3.12 A

n-Propyl 471.5 80 3.13 A

i-Propyl 471.5 96 3.14 A

497.5 103 3.15 A

—CONH₂ 472.4 190 3.16 A

578.6 213 3.17 A

556.5 203 3.18 A

556.5 165 3.19 A

488.5 198 3.20 A

538.6 213 3.21 A

502.6 185 3.22 A

516.6 171 3.23 A

—CH₂CH₂Cl 474.9 195 3.24 A

—CH₃ 426.5 225 3.25 A

n-Propyl 454.5 3.26 A

i-Propyl 454.5 3.27 A

Ethyl 440.5 3.28 A

480.6 205 3.29 A

—CONH₂ 455.5 129

Examples 3.15 and 3.29 are produced analogously to Example 3.0 with useof trimethylsilyl isocyanate.

EXAMPLE 3.30 Production of2-{[2-(3,3-Dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-isoquinolinyl)-benzamide

100 mg (0.23 mmol) of2-[(2-bromopyridin-4-ylmethyl)-amino]-N-(3-isoquinolinyl)-benzamide isheated in 2 ml of dioxane with 89 mg (0.28 mmol) of cesium carbonate, 61mg (0.69 mmol) of N,N-dimethylurea, 4.7 mg (0.0046 mmol) ofdipalladium-tribenzylidene acetone and 7.9 mg (0.014 mmol) of Xanthphosunder a cover gas and in a moisture-free environment for 9 hours to abath temperature of 100° C. It is then mixed with 20 ml of methylenechloride, suctioned off and concentrated by evaporation. The residue ischromatographed on silica gel with ethyl acetate as an eluant. 24 mg(24% of theory) of2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-isoquinolinyl)-benzamideis obtained.

(MS (CI): 441 (M⁺+H))

Similarly produced are also the following compounds:

[Key: Typ = Type] Melting Point [° C.] or MS Exam- Molar Peak ple No.Type R¹ R⁹ R¹⁰ MW (m/e) 3.31 A

H H 412.5 222 3.32 A

H H 429.4 3.33 A

Me H 415.46 3.34 A

Me H 415.46 110–113 3.35 A

Me H 429.48 230–232 3.36 A

Me H 429.48 130–133 3.37 A

Me H 457.54 3.38 A

H 455.52 3.39 A

H 455.52 3.40 A

Me Me 443.51 3.41 A

Me Me 443.51 3.42 A

Me H 443.51 3.43 A

Me H 457.54 3.44 A

Me H 443.51 3.45 A

Me H 457.54 3.46 A

Me H 457.54 3.47 A

Me H 473.53 199.5 3.48 A

Me H 443.51 208.8 3.49 A

Me H 453.50 242 3.50 A

Me H 429.48 m/e 429 3.51 A

Me H 429.48 205.1 3.52 A

cycl.Prop H 455.52 192 3.53 A

cycl.Prop H 455.52 216 3.54 A

Me H 473.53 247 3.55 A

H 499.57 3.56 A

Me H 473.53 3.57 A

Me H 473.53 3.58 B

Me H 429.48 3.59 B

Me H 429.48 3.60 A

Me H 454.48 3.61 A

Me H 454.48 3.62 A

Me H 486.53 3.63 A

—(CH₂)₂—O—CH₃ H 473.53 3.64 A

—(CH₂)₂N(CH₃)₂ H 486.58 3.65 A

H 528.61 3.66 A

—(CH₂)₂—O—CH₃ H 473.53 3.67 A

—(CH₂)₂N(CH₃)₂ H 486.58 3.68 A

H 528.61 3.69 A

Me H 454.49

EXAMPLE 4.0 Production of2-[(2-Methanesulfonylamino-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamide

90 mg (0.2 mmol) of2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamideand 23 mg (0.24 mmol) of methanesulfonic acid amide are introduced into5 ml of dioxane and mixed in succession with 4 mg (0.02 mmol) ofcopper(I) iodide, 85 mg (0.4 mmol) of potassium phosphate and 2 mg (0.02mmol) of ethylenediamine. After 1 hour of stirring at a bath temperatureof 120° C., it is diluted with 20 ml of water and concentrated byevaporation. It is then made alkaline with ammonia and shaken out threetimes with 25 ml each of ethyl acetate. The collected organic phase iswashed with water, dried, filtered and concentrated by evaporation. Theresidue is made crystalline with ethyl acetate and a little hexane,stirred and suctioned off. 24 mg (26% of theory) of2-[(2-methanesulfonyl-amino-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamidewith a melting point of 214.5° C. is obtained.

Similarly produced are:

Melting Point [° C.] or MS Example Molar Peak No. R¹ R² MW (m/e) 4.1

526.54 259.2 4.2

541.55 >300 4.3

610.53 248.6 4.4

—SO₂CF₃ 518.44 238.9 4.5

—SO₂CH₃ 447.52 m/e: 447 4.6

562.52 252.5 4.7

598.64 231 4.8

567.01 255.2 4.9

550.06 234.7 4.10

540.56 245.7 4.11

540.56 194.8 4.12

498.57 256 4.13

512.59 219

EXAMPLE 5.0 Production of2-[(2-Bismethanesulfonylamino-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamide

193 mg (0.5 mmol) of2-[(2-amino-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamideis mixed in 3 ml of dichloromethane with 69 mg (0.6 mmol) ofmethanesulfonic acid chloride and 61 mg (0.6 mmol) of triethylamine andstirred together for 1.5 hours at room temperature. Then, it is washedonce with dilute sodium bicarbonate solution, dried, filtered andconcentrated by evaporation. The residue is chromatographed via flashchromatography (5 g of Isolute) with a gradient of cyclohexane:ethylacetate=100:0 to 50:50 as an eluant. 80 mg (30% of theory) of2-[(2-bismethanesulfonylamino-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamideis obtained as a resin.

(MS: m/e 542)

EXAMPLE 6.0 Production of2-[(2-Butyrylamino-pyridin-4-ylmethyl)-amino]-N-(3-isoquinolinyl)-benzamide

100 mg (0.23 mmol) of2-[(2-bromopyridin-4-ylmethyl)-amino]-N-(3-isoquinolinyl)-benzamide isheated in 1 ml of dioxane with 89 mg (0.28 mmol) of cesium carbonate, 24mg (0.69 mmol) of butyramide, 4.7 mg (0.0046 mmol) ofdipalladium-tribenzylidene acetone and 7.9 mg (0.014 mmol) of Xanthphosunder a cover gas and in a moisture-free environment for 25 hours to abath temperature of 90° C. It is then mixed with 20 ml of methylenechloride, suctioned off and concentrated by evaporation. The residue ischromatographed on silica gel first with hexane, then with hexane:ethylacetate=8:2 and then with hexane:ethyl acetate=1:1 as an eluant. 45 mg(42% of theory) of2-[(2-butyrylamino-pyridin-4-ylmethyl)-amino]-N-(3-isoquinolinyl)-benzamidewith a melting point of 173° C. is obtained.

Similarly produced are:

Melting Point [° C.] or MS Example Molar Peak No. R¹ R² MW (m/e) 6.1

—COn-Prop 456.47 168 6.2

—COMe 411.46 220 6.3

—COEt 425.49 183 6.4

—COn-Bu 453.54 167 6.5

437.50 218 6.6

549.63 212 6.7

453.54 112 6.8

529.64 219 6.9

523.59 215 6.10

—COt-Bu 453.54 91 6.11

546.59 111 6.12

—COOEt 441.50 185 6.13

COMe 428.41 185 6.14

CO-cycl.Prop 426.48 210–212 6.15

CO-cycl.Prop 426.48 127–128 6.16

558.48 6.17

COPh 490.48 6.18

508.47 6.19

CO-cycl.Prop 440.51 114–115 6.20

CO—(CH₂)₄—OH 469.54 136 6.21

—COOEt 444.49 205–210 6.22

—COOEt 430.47 6.23

CO₂CH₂(i-Prop) 472.55 187 6.24

CO₂(i-Prop) 458.52 204 6.25

CO-cycl.Prop 440.51 105–107 6.26

491.47 6.27

COOEt 430.47 213 6.28

COOEt 444.49 194–196 6.29

CO-cycl-Prop 545.45 213 6.30

CO-t-Bu 470.49 155 6.31

—CO—CH₂—O—(CH₂)₂OH 471.51 86

EXAMPLE 6.32

Similarly produced is:

2-{[2-(Acetyl-methyl-amino)-pyridin-4-ylmethyl]-amino}-N-isoquinolin-3-yl-benzamide

Melting point 71° C.

EXAMPLE 7.0 Production of2-{[2-(2-Oxo-pyrrolidin-1-yl)-pyridin-4-ylmethyl]-amino}-N-(3-tribenzylidene

156 mg (0.5 mmol) of2-{[2-(2-oxo-pyrrolidin-1-yl)-pyridin-4-ylmethyl]-amino}-benzoic acid ismixed in 5 ml of dimethylformamide with 0.12 ml (1 mmol) of3-aminobenzotrifluoride, 228 mg (0.6 mmol) of HATU(N-dimethylamino-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanammoniumhexafluorophosphate-N-oxide)and 0.14 ml of N-methylmorpholine, and it is stirred overnight at roomtemperature. It is diluted with ethyl acetate and washed in successionwith saturated sodium bicarbonate solution, water and saturated commonsalt solution. The organic phase is dried, filtered and concentrated byevaporation. The residue is chromatographed on Isolute as a mobilesolvent. 95 mg (42% of theory) of2-{[2-(2-oxo-pyrrolidin-1-yl)-pyridin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-benzamideis obtained.

(MS: m/e 454)

Similarly produced are:

R², R³, Y and Z = G Melting Point [° C.] Example or MS Molar Peak No. R¹G MW (m/e) 7.1

439.5 189° C. 7.2

455.4 m/e 455 7.3

469.5 209 7.4

438.5 154 7.5

435.5 217.3 7.6

426.48 195–200 7.7

426.48 105–110

EXAMPLE 8.0

Produced similarly to Example 6.0 is:

2-{[2-(2-Hydroxymethyl-5-oxo-pyrrolidin-1-yl)-pyridin-4-ylmethyl]-amino}-N-isoquinolin-3-yl-benzamide

Similarly produced to this are:

Melting Point [° C.] Example or MS Molar Peak No. R¹ G MW (m/e) 8.1

467.53 98° C. 8.2

467.53 76° C. 8.3

467.53 95° C. 8.4

447.50 86° C. 8.5

481.94 186° C.  8.6

440.51 196–198 8.7

440.51 100 (Dec.) 8.8

440.51 159 8.9

440.51 8.10

441.49 8.11

441.49 8.12

441.49 8.13

441.49 8.14

454.33 8.15

454.33 8.16

454.33 8.17

454.33 8.18

468.56 8.19

468.56

EXAMPLE 9.0 Production of2-{[2-(2,5-Dioxo-pyrrolidin-1-yl)-pyridin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-benzamide

193 mg (0.5 mmol) of2-[(2-amino-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamideis mixed in 20 ml of dichloromethane with 0.21 ml (1.5 mmol) oftriethylamine, and it is mixed at room temperature drop by drop with asolution of 93 mg (0.6 mmol) of succinic acid dichloride in 3 ml ofmethylene chloride. After stirring overnight at room temperature, it isdiluted with methylene chloride and washed in succession with water,saturated sodium bicarbonate solution and saturated common saltsolution. Then, the organic phase is dried, filtered and concentrated byevaporation. The residue is chromatographed on Isolute (SepartisCompany) with a gradient of methylene chloride:ethanol=100:0 to 95:5.120 mg (51% of theory) of2-{[2-(2,5-dioxo-pyrrolidin-1-yl)-pyridin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-benzamideis obtained.

(MS: m/e 468)

Similarly produced is:

EXAMPLE 9.12-{[2-(3,5-Dioxo-morpholin-4-yl)-pyridin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-benzamide

Melting point 201.9° C.

EXAMPLE 10.0 Production of2-[(2-(3-Chloropropanesulfonylamino-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamide

135 mg (0.35 mmol) of2-[(2-amino-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamideis mixed in 10 ml of dichloromethane with 62 mg (0.35 mmol) of3-chloropropanesulfonic acid chloride and 49 μl (0.35 mmol) oftriethylamine, and it is stirred for 2 hours at room temperature. Then,it is washed once with saturated sodium bicarbonate solution, filteredand concentrated by evaporation. The residue is chromatographed viaflash chromatography (5 g of Isolute) with a gradient ofdichloromethane:ethanol=100:0 to 90:10 as an eluant. 67 mg (36% oftheory) of2-[(2-(3-chloropropanesulfonylamino-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamideis obtained.

(MS (CI): 491 (100%, M⁺+H—HCl))

EXAMPLE 11.0 Production of2-{[2-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-pyridin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-benzamide

58 mg (0.11 mmol) of2-[(2-(3-chloropropanesulfonylamino-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamideis suspended in 5 ml of ethanol and mixed with 5 mg of sodium hydride(55% in mineral oil). The mixture is refluxed for 1 hour, mixed with 10ml of water and extracted with ethyl acetate. The aqueous phase issaturated with sodium sulfate and extracted repeatedly by stirring withethyl acetate overnight. After the combined extracts are concentrated byevaporation, 50 mg (93% of theory) of2-{[2-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-pyridin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-benzamideis obtained.

(MS (CI): 491 (100%, M⁺+H))

EXAMPLE 12.0N-[2-(2-Hydroxy-ethyl)-2H-indazol-5-yl]-2-{[2-(3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-benzamide

50 mg (0.11 mmol) ofN-[2-(2-methoxy-ethyl)-2H-indazol-5-yl]-2-{[2-(3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-benzamideis introduced into 5 ml of methylene chloride and mixed drop by dropunder argon and in a moisture-free environment at −78° C. with 0.56 mlof boron tribromide (1 molar in methylene chloride). It is stirred for15 more minutes, the cold bath is removed, and it then is stirred for 2more hours. Then, it is mixed with water, the methylene chloride isdrawn off, made alkaline with sodium bicarbonate solution and extractedtwice with 15 ml each of ethyl acetate. The collected organic phase isdried, filtered, and concentrated by evaporation. The residue ischromatographed on silica gel with a gradient of methylenechloride:ethanol=100:0 to 90:10 as an eluant, and 27 mg ofN-[2-(2-hydroxy-ethyl)-2H-indazol-5-yl]-2-{[2-(3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-benzamideis obtained.

Similarly produced from the corresponding methoxy compounds are:

Melting Point [° C.] Example or MS Molar Peak No. R¹ R² MW (m/e) 12.1

459.51 187 12.2

459.51 228 12.3

459.51 229 12.4

459.51 12.5

459.51 220

Production of Intermediate Compounds EXAMPLE A

If the production of intermediate compounds is not described, the latterare known or can be produced analogously to known compounds or toprocesses that are described here.

Stage 1

a) Production of 2-Bromopyridine-5-carbaldehyde

is carried out according to F. J. Romero-Salguerra et al. THL 40,859(1999).b) Production of 2-Bromo-isonicotinic Acid

160 g (0.93 mol) of 2-bromo-4-methyl-pyridine is added in drops to 152 g(0.96 mol) of potassium permanganate in 4 l of water. Then, it isstirred under reflux for one hour before 152 g (0.96 mol) of potassiumpermanganate is added once more. After two additional hours of stirringunder reflux, it is suctioned off in a hot state over Celite and washedwith water. The aqueous phase is shaken out three times withdichloromethane. The aqueous phase is concentrated by evaporation toone-half its original volume, and the pH is set at 2 with concentratedhydrochloric acid. The precipitated solid is suctioned off and dried at70° C. in a vacuum. 56.5 g of white solid product accumulates.

Production of 2-Bromo-4-hydroxymethyl-pyridine

30.2 ml (295 mmol) of triethylamine is added to 56.5 g (280 mmol) of2-bromo-isonicotinic acid in 1.2 l of THF. Then, it is cooled to −10° C.and mixed drop by drop with 38.2 ml (295 mmol) of isobutylchloroformate. After stirring has been continued for one hour at −10°C., it is cooled to −70° C. and mixed drop by drop with 590 ml (590mmol) of LiAlH₄ solution (1 M in THF). After stirring is continued forone hour at −70° C., it is allowed to reach −40° C. 600 ml of 50% aceticacid is added. It is stirred overnight at room temperature. Theinsoluble components are suctioned off, and the filtrate is concentratedby evaporation. The residue is purified on silica gel with hexane andhexane/ethyl acetate 1:1. 28.0 g of white solidifying oil accumulates.

Production of 2-Bromo-4-formyl-pyridin

149 g (1714 mmol) of manganese dioxide is added in measured quantitiesto 28.0 g (148.9 mmol) of 2-bromo-4-hydroxymethyl-pyridine in 500 ml ofdichlormethane within 6 hours. Then, stirring is continued at roomtemperature for 48 hours. It is suctioned off over Celite andconcentrated by evaporation. 16.4 g of solidifying white oilaccumulates.

2-Bromo-4-formyl-pyridine can also be produced according to THL 42, 6815(2001) from 2-bromo-4-picoline in two stages.

Stage 2

Production of2-[(6-Bromo-pyridin-3-ylmethyl)-amino]-N-isoquinolin-3-yl-benzamide

3.46 g (13.17 mmol) of 2-amino-N-isoquinolin-3-yl-benzamide isintroduced into 50 ml of methanol, mixed with 1.5 ml of glacial aceticacid as well as 2.45 g (13.17 mmol) of 2-bromopyridine-5-carbaldehydeand stirred for 24 hours under argon and in a moisture-free environmentat room temperature. Then, it is mixed with 828 mg (13.17 mmol) ofsodium cyanoborohydride and stirred for another 24 hours at roomtemperature. After concentration by evaporation under vacuum, theresidue is taken up in dilute sodium bicarbonate solution and suctionedoff. The residue that is obtained is absorptively precipitated in alittle ethyl acetate and suctioned off repeatedly. The residue that isobtained in this case is chromatographed on silica gel with hexane:ethylacetate=1:1 as an eluant. 3.27 g (57% of theory) of2-[(6-bromo-pyridin-3-ylmethyl)-amino]-N-isoquinolin-3-yl-benzamide isobtained.

Similarly produced are:

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-isoquinolin-3-yl-benzamide

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamide

EXAMPLE B

1^(st) Stage

Production of 2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-benzoic Acid MethylEster

6.04 g (40 mmol) of anthranilic acid methyl ester in 600 ml of methanolis mixed with 3.2 ml of acetic acid and 7.4 g (40 mmol) of2-bromopyridine-4-carbaldehyde and stirred overnight at 40° C. 3.8 g (60mmol) of sodium cyanoborohydride is added thereto and stirred overnightat 40° C. 3.8 g (60 mmol) of sodium cyanoborohydride is added again andstirred over the weekend at 40° C. It is mixed with water and largelyconcentrated by evaporation. The aqueous phase is extracted with ethylacetate, and the combined organic phases are dried, filtered andconcentrated by evaporation. The crude product is chromatographed onsilica gel with a gradient that consists of hexane and hexane/ethylacetate 1:3 and hexane/ethyl acetate 1:1 as an eluant. 10.0 g (78% oftheory) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid methylester is obtained as a colorless oil.

EXAMPLE C

1^(st) Stage

Production of 2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-benzoic Acid

10.0 g (31.2 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoicacid methyl ester is dissolved in 290 ml of ethanol and mixed with 31.2ml of 2 M sodium hydroxide solution. After having been stirred overnightat room temperature, the ethanol is drawn off, and the aqueous phase isshaken out with ethyl acetate. The aqueous phase is acidified withconcentrated hydrochloric acid. The precipitate that is formed issuctioned off and dried. 5.93 g (62%) of2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid accumulates in theform of a white solid.

2^(nd) Stage

Production of2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benzamide

0.500 g (1.6 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoicacid, 0.471 g (3.2 mmol) of 2-methyl-2H-indazol-6-ylamine, 0.4 ml (3.68mmol) of N-methylmorpholine and 0.729 g (1.92 mmol) ofO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate(HATU) in 25 ml of dimethylformamide are stirred for 16 hours at roomtemperature. The dimethylformamide is drawn off in an oil pump vacuum.The remaining residue is drawn off in saturated sodium bicarbonatesolution. It is extracted three times with ethyl acetate, and thecombined organic phases are dried, filtered and concentrated byevaporation. The residue is chromatographed on silica gel with agradient that consists of hexane:acetone=100:0 to 50:50 as an eluant.0.669 g (96% of theory) of2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benzamideis obtained in the form of a beige foam.

Similarly produced are also the following compounds:

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(1-methyl-1H-indazol-6-yl)-benzamide

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(1H-indazol-6-yl)-benzamide

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(1H-indazol-5-yl)-benzamide

EXAMPLE D

Stage 1

Production of2-{[2-(2-Oxo-pyrrolidin-1-yl)-pyridin-4-ylmethyl]-amino}-benzoic AcidMethyl Ester

870 mg (2.78 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoicacid methyl ester, 53 mg (0.28 mmol) of copper (I) iodide, 1.126 g (5.5mmol) of potassium phosphate and 0.26 ml (3.6 mmol) of pyrrolidin-2-oneare refluxed in 15 ml of dioxane for 8 hours. After water is added, thedioxane is distilled off in a vacuum, made alkaline with about 12%ammonia solution and shaken out several times with ethyl acetate. Thecollected ethyl acetate phase is washed, dried, filtered andconcentrated by evaporation. As a residue, 700 mg (77% of theory) of2-{[2-(2-oxo-pyrrolidin-1-yl)-pyridin-4-ylmethyl]-amino}-benzoic acidmethyl ester is obtained as a crude product, which is used withoutfurther purification in the next stage.

Similarly produced are:

Melting Point [° C.] or MS Molar Peak G MW (m/e)

327.3

326.4

341.4Stage 3

Production of2-{[2-(2-Oxo-pyrrolidin-1-yl)-pyridin-4-ylmethyl]-amino}-benzoic Acid

700 mg (2.15 mmol) of2-{[2-(2-oxo-pyrrolidin-1-yl)-pyridin-4-ylmethyl]-amino}-benzoic acidmethyl ester is mixed in 15 ml of methanol with 2.7 ml of 1N sodiumhydroxide solution and refluxed for 1 hour. After the methanol isdistilled off in a vacuum, it is diluted with water and shaken once withethyl acetate. The aqueous phase is mixed with 5 ml of 1 mol citric acidsolution and stirred overnight. The solid precipitation is suctioned offand very quickly dried. 600 mg of2-{[2-(2-oxo-pyrrolidin-1-yl)-pyridin-4-ylmethyl]-amino}-benzoic acid,which is used as a crude product in the next stage, is obtained.

Similarly produced are:

R², R³, Y and Z = G Melting Point [° C.] or MS Molar Peak G MW (m/e)

313.3

312.3

326.4

EXAMPLE E Production of2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(1-methyl-1H-indazol-5-yl)-benzamideand2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-5-yl)-benzamide

4.22 g (10 mmol) of2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(1H-indazol-5-yl)-benzamide ismixed in 30 ml of dimethylformamide while being cooled with ice with 3.6g (11 mmol) of cesium carbonate and 0.68 ml (11 mmol) of methyl iodide,and it is stirred overnight at room temperature. It is then stirred into250 ml of ice-cold water, stirring is continued for 15 minutes, and itis suctioned off. The filter cake is very quickly dried andchromatographed on silica gel with a gradient of ethyl acetate:hexane1:1 to 100:0 as an eluant. 1.79 g (41% of theory) of2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(1-methyl-1H-indazol-5-yl)-benzamidewith a melting point of 173.8° C. as well as 830 mg (19% of theory) of2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-5-yl)-benzamidewith a melting point of 183.8° C. are obtained.

Similarly produced are:

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(1-isopropyl-1H-indazol-5-yl)-benzamide,

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(2-isopropyl-2H-indazol-5-yl)-benzamide,

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(1-ethyl-1H-indazol-5-yl)-benzamide,

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(2-ethyl-2H-indazol-5-yl)-benzamide,

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(1-[2-methoxyethyl]-1H-indazol-5-yl)-benzamide,

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(2-[2-methoxyethyl]-2H-indazol-5-yl)-benzamide,

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(1-[cyanomethyl]-1H-indazol-5-yl)-benzamide,

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(2-[cyanomethyl]-2H-indazol-5-yl)-benzamide,

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(1-[2-dimethylaminoethyl]-1H-indazol-5-yl)-benzamide,

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(2-[2-dimethylaminoethyl]-2H-indazol-5-yl)-benzamide,

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(1-methyl-1H-indazol-6-yl)-benzamide,

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benzamide,

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(1-isopropyl-1H-indazol-6-yl)-benzamide,

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(2-isopropyl-2H-indazol-6-yl)-benzamide,

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(1-ethyl-1H-indazol-6-yl)-benzamide,

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(2-ethyl-2H-indazol-6-yl)-benzamide,

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(1-[2-methoxyethyl]-1H-indazol-6-yl)-benzamide,

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(2-[2-methoxyethyl]-2H-indazol-6-yl)-benzamide,

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(1-[cyanomethyl]-1H-indazol-6-yl)-benzamideand

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(2-[cyanomethyl]-2H-indazol-6-yl)-benzamide.

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(1-[2-dimethylaminoethyl]-1H-indazol-6-yl)-benzamideand

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(2-[2-dimethylaminoethyl]-2H-indazol-6-yl)-benzamide.

The sample applications below explain the biological action and the useof the compounds according to the invention without the latter beinglimited to the examples.

Solutions Required for the Tests

Stock solutions

-   Stock solution A: 3 mmol of ATP in water, pH 7.0 (−70° C.)-   Stock solution B: g-33P-ATP 1 mCi/100 μl-   Stock solution C: poly-(Glu4Tyr) 10 mg/mi in water    Solution for dilutions-   Substrate solvent: 10 mmol of DTT, 10 mmol of manganese chloride,    100 mmol of magnesium chloride-   Enzyme solution: 120 mmol of tris/HCl, pH 7.5, 10 μM of sodium    vanadium oxide

Sample Application 1 Inhibition of the KDR- and FLT-1 Kinase Activity inthe Presence of the Compounds According to the Invention

In a microtiter plate (without protein binding) that tapers to a point,10 μl of substrate mix (10 μl of volume of ATP stock solution A+25 μCiof g-33P-ATP (about 2.5 μl of stock solution B) +30 μl of poly-(Glu4Tyr)stock solution C+1.21 ml of substrate solvent), 10 μl of inhibitorsolution (substances corresponding to the dilutions, 3% DMSO insubstrate solvent as a control) and 10 μl of enzyme solution (11.25 μgof enzyme stock solution (KDR or FLT-1 kinase) are added at 4° C. in1.25 ml of enzyme solution (dilute). It is thoroughly mixed andincubated for 10 minutes at room temperature. Then, 10 μl of stopsolution (250 mmol of EDTA, pH 7.0) is added, mixed, and 10 μl of thesolution is transferred to a P 81 phosphocellulose filter. Then, it iswashed several times in 0.1 M phosphoric acid. The filter paper isdried, coated with Meltilex and measured in a microbeta counter.

The IC50 values are determined from the inhibitor concentration, whichis necessary to inhibit the phosphate incorporation to 50% of theuninhibited incorporation after removal of the blank reading(EDTA-stopped reaction).

The results of the kinase inhibition IC50 in μM are presented in thetable below.

Sample Application 2 Cytochrome P450 Inhibition

The Cytochrome P450 inhibition was performed according to thepublication of Crespi et al. (Anal. Biochem., 248, 188–190 (1997)) withuse of the baculovirus/insect cell-expressed, human Cytochrome P 450isoenzyme (3A4).

The results are presented in the following table.

VEGFR II (KDR) Cytochrome P450 Example No. [nM] Isoenzyme 3A4 μM 2.54 53.6 from WO 00/27819 38    180 4.6 from WO 00/27820 1.14 52 >30 3.24 1214 3.30 10 5.5 6.2  41 >30 6.22 24 10 6.27 8 10 6.32 65 11

The superior action of the compounds according to the invention comparedto the known compounds can be seen clearly from the result.

1. A compound of formula I

in which X stands for CH, W stands for hydrogen or fluorine, A, B, D,and E each stand for a carbon atom, and Q, stands fo a nitrogen atom, R¹stands for indazolyl, which is optionally substituted in one or moreplaces in the same way or differently with halogen, hydroxy,C₁–C₁₂-alkyl, C₃–C₆-cycloalkyl, C₃–C₆-alkenyl, C₂–C₆-alkinyl,aralkyloxy, C₁–C₁₂-alkoxy, halo-C₁–C₆-alkyl, cyano-C₁–C₆-alkyl or withthe group ═O, —SO₂R⁶ or —OR⁵, whereby the C₁–C₆-alkyl optionally alsocan be substituted with the group —OR⁵ or —NR⁹R¹⁰, Y and Z, in each caseindependently of one another, stand for a bond or for the group ═CO, ═CSor ═SO₂, R² and R³, independently of one another, stand for hydrogen orfor the group —CONR⁹R¹⁰, —SO²R⁶, —COR¹¹, —COC₁–C₆-alkyl,—CO—C₁–C₆-alkyl-R¹¹, —NR⁹R¹⁰ or for C₁–C₆-alkyl, C₃–C₁₀-cycloalkyl,C₃–C₆-cycloalkenyl, or aryl that is optionally substituted in one ormore places in the same way or differently with halogen, cyano,C₁–C₁₂-alkyl, C₁–C₁₂-alkoxy, hydroxy-C₁–C₆-alkyl, halo-C₁–C₆-alkyl orwith the group —NR⁷R⁸, —OR⁵, —C₁–C₆-alkyl-OR⁵, —SR⁴, —SOR⁴ or —SO₂R⁶, R⁴stands for C₁–C₁₂-alkyl, or aryl, R⁵ stands for hydrogen, C₁–C₁₂-alkyl,C₃–C₁₀-cycloalkyl, C₁–C₁₂-alkoxy, halo-C₁–C₁₂-alkyl, orhalo-C₃–C₆-cycloalkyl, R⁶ stands for hydrogen, C₁–C₁₂-alkyl,halo-C₁–C₆-alkyl, or aryl, or for the group —NR⁹R¹⁰, whereby the aryl isoptionally substituted in one or more places in the same way ordifferently with C₁–C₁₂-alkyl, C₁–C₆-alkoxy, halogen orhalo-C₁–C₆-alkoxy, R⁷ and R⁸, independently of one another, stand forhydrogen or C₁–C₁₂-alkyl, R⁹ and R¹⁰, independently of one another,stand for hydrogen, C₁–C₆-alkyl, C₂–C₆-alkenyl, aryl, C₃–C₈-cycloalkylor for the group —CONR⁷R⁸, or for C₁–C₁₂-alkyl that is optionallysubstituted in one or more places in the same way or differently witharyl, hydroxy, halogen, C₁–C₁₂-alkoxy, or for the group —NR⁷R⁸, wherebythe aryl optionally substituted in one or more places in the same way ordifferently with C₁–C₆-alkoxy or halo-C₁–C₆-alkyl, and R¹¹ stands forC₁–C₆-alkyl, C₁–C₆-alkoxy, hydroxy-C₁–C₆-alkyl, hydroxy-C₁–C₆-alkoxy,C₃–C₆-cycloalkyl, phenyl, biphenyl or naphthyl, whereby the phenyl isoptionally substituted in one or more places in the same way ordifferently with C₁–C₆-alkyl, or halo-C₁–C₆-alkyl, or an isomer,diastereomer, tautomers or salt thereof.
 2. A compound of formula I,according to claim 1, in which W stands for hydrogen, A, B, D, E and Qas a ring together stand for pyridyl, Y and Z, in each caseindependently of one another, stand for a bond, R⁴ stands forC₁–C₆-alkyl, or aryl, R⁵ stands for hydrogen, C₁–C₆-alkyl,halo-C₁–C₆-alkyl, C₁–C₁₂-alkoxy, C₃–C₁₀-cycloalkyl orhalo-C₃–C₆-cycloalkyl, R⁶ stands for hydrogen, C₁–C₆-alkyl,halo-C₁–C₆-alkyl, or aryl, or for the group —NR⁹R¹⁰, whereby the aryl isoptionally substituted in one or more places in the same way ordifferently with C₁–C₆-alkyl, C₁–C₆-alkoxy, halogen orhalo-C₁–C₆-alkoxy, and R⁷ and R⁸, independently of one another, standfor hydrogen or C₁–C₆-alkyl, or an isomer, diastereomer, tautomer andsalt thereof.
 3. A compound of formula I, according to claims 1, inwhich W stands for hydrogen, A, B, D, E, and Q as a ring together standfor pyridyl, R¹ stands for indazolyl, which is optionally substituted inone or more places in the same way or differently with halogen, hydroxy,C₁–C₆-alkyl, C₂–C₆-alkinyl, C₁–C₆-alkoxy, halo-C₁–C₆-alkyl, orcyano-C₁–C₆-alkyl, whereby C₁–C₆-alkyl optionally also can besubstituted with the group —OR⁵ or —NR⁹R¹⁰, Y and Z, in each caseindependently of one another, stand for a bond, or for the group ═CO, R²and R³, independently of one another, stand for hydrogen or for thegroup —CONR⁹R¹⁰, —SO₂R⁶, —COR¹¹, —COC₁–C₆-alkyl, —CO—C₁–C₆-alkyl-R¹¹,—NR⁹R¹⁰ or for C₁–C₆-alkyl or phenyl that is optionally substituted inone or more places in the same way or differently with the group —NR⁷R⁸or —OR⁵, R⁵ stands for hydrogen or C₁–C₆-alkyl, R⁶ stands for hydrogen,C₁–C₆-alkyl, halo-C₁–C₆-alkyl, phenyl, or benzyl, whereby the phenyl, orbenzyl, are optionally substituted in one or more places in the same wayor differently with C₁–C₆-alkyl, C₁–C₆-alkoxy, halogen orhalo-C₁–C₆-alkoxy, R⁷ and R⁸, independently of one another, stand forhydrogen or C₁–C₆-alkyl, and R⁹ and R¹⁰, independently of one another,stand for hydrogen, C₁–C₆-alkyl, C₂–C₆-alkenyl, phenyl, biphenyl,C₃–C₈-cycloalkyl, naphthyl or for the group —CONR⁷R⁸ or for C₁–C₆-alkylthat is optionally substituted in one or more places in the same way ordifferently with phenyl, hydroxy, halogen, C₁–C₁₂-alkoxy, or with thegroup —NR⁷R⁸, whereby the phenyl is optionally substituted in one ormore places in the same way or differently with C₁–C₆-alkoxy orhalo-C₁–C₆-alkyl, or an isomer, diastereomer, tautomer or salt thereof.